The present invention relates to a novel class of compounds which have structures related to certain naturally occurring and synthetic chalcones, as well as to methods for the preparation of such compounds and to pharmaceutical uses thereof.
The compound 1,3-diphenyl-2-propene-1-one is known by the trivial name xe2x80x9cchalconexe2x80x9d. Many naturally occurring flavanoids share structural features with chalcone and are referred to by the generic term xe2x80x9cchalconesxe2x80x9d. Also, certain flavanoids, including ones which are also classified as chalcones, have recently been demonstrated to have anticancer activity (Cancer Research 48, 5754, 1988) and chemopreventive activity in some tumours (J. Nat. Prod. 53, 23, 1990).
In particular, quercetin, an ubiquitous flavonoid found in plants, has been shown to act on the proliferation of human leukaemic cells (Br. J. Haematology, 75, 489, 1990) and on other cell lines (Br. J. Cancer, 62, 94, 942, 1990; Int. J. Cancer, 46, 112. 1990; Gynaecologic Oncology, 45, 13, 1992) and to possess a synergic action with common antiblastic drugs.
In addition, some natural or synthetic chalcones, described in our International Patent Publication No. WO 91/17749, and in International Patent Publication No. WO 96/19209 (Baylor College of Medicine), have proved to have a significant antiproliferation activity on a variety of different cell lines.
Thus according to one aspect of the present invention, there is provided a compound of Formula (I): 
The action in vivo of these polyphenol substances is certainly much more complicated. All these compounds are generally characterised by an almost complete insolubility in water and, in vivo, by a very poor bioavailability linked to a rapid metabolism of phenols and a marked affinity for lipids and proteins.
Surprisingly, it has now been found that certain novel chalcones, chalcone derivatives and chalcone analogues, and in particular, compounds in which the phenyl ring in the 1-position is substituted or replaced by rings containing one or more heteroatoms, possess a greater antiproliferation activity both on sensitive cancerous cells and on cells which are resistant to common chemotherapeutic drugs, including the latest generation anti-neoplastic agents, paclitaxel and docetaxel.
Thus according to one aspect of the present invention, there is provided a compound of Formula (I): 
or a pharmaceutically acceptable salt or solvate thereof wherein:
Ar represents
a substituted or unsubstituted, (preferably aromatic), carbocyclic or heterocyclic group, said carbocyclic or heterocyclic group containing from 5 to 10 ring atoms, said ring atoms forming one or two rings, wherein the or each ring contains 5 or 6 ring atoms, any heteroatoms being selected from N, O and S, any substituents on the Ar group being independently selected from the group consisting of.
(a) Cl, (b) Br, (c) F, (d) OH, (e) NO2, (f) CF3, (g) C1-4lower alkyl (in particular CH3), (h) SCH3, (i) NHCOCH3, (j) N(R6) (R8) wherein R6 and R8 are the same or different and each represents H or lower C1-4alkyl, (k) OR10 wherein R10 represents a saturated or unsaturated lower C1-6 straight or branched hydrocarbyl group which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from:
Cl, Br, F, OMe, NO2 and CF3, and (I) xe2x80x94OCOR11, wherein R11 represents a saturated or unsaturated lower C1-6 straight or branched hydrocarbyl group or a phenyl group;
R represents
OH, OR10 or OCOR11, wherein R10 and R11 are as defined above; and
(A) R2 and R3 are each independently selected from:
(i) a substituted or unsubstituted, preferably aromatic, carbocyclic or heterocyclic group containing from 5 to 10 ring atoms, said ring atoms forming one or two rings, wherein the or each ring contains 5 or 6 ring atoms, any heteroatoms being selected from N, O and S, any substituents being independently selected from the group consisting of:
Cl, Br, F, OH, NO2, CF3, C1-4 lower alkyl (in particular CH3), SCH3, NHCOCH3, N(R6)(R8), OR10 and OCOR11, wherein R6, R8, R10 and R11 are as defined above,
(ii) Cl, (iii) Br, (iv) F, (v) OH, (vi) NO2, (vii) a saturated or unsaturated lower Cl straight or branched hydrocarbyl group which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from Cl, Br, F, OMe, NO2 and CF3, (viii) NHCOCH3, (ix) N(R6)(R8), (x) SR10, (xi) OR10, and (xii) OCOR11, wherein R6, R8, R10 and R11 are as defined above; or
(B) R2 and R3 taken together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring having 5 or 6 ring atoms, any heteroatom being selected from N, O or S, said carbocyclic or heterocyclic ring being saturated or unsaturated, and being unsubstituted or substituted with one or more substituents selected from Cl, Br, F, OH, NO2, CF3, C1-6 lower alkyl, SCH3, NHCOCH3, N(R6)(R8), OR10 and OCOR11, wherein R6, R8, R10 and R11 are as defined above.
Compounds described above, wherein R2 and R3 taken together with the carbon atoms to which they are attached form a ring, may be represented by Formula (IA): 
wherein the substituents R and Ar are as defined above, and R2 and R3 taken together represent Ring Q, said Ring Q being a five- or six-membered, preferably aromatic, carbocyclic or heterocyclic ring, any heteroatom being selected from N, O, or S, said ring being unsaturated or saturated, said carbocyclic ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from: Cl, Br, F, OH, NO2, CF3, C1-4 lower alkyl, SCH3, NHCOCH3, N(R6)(R8), OR10 and OCOR11, wherein R8, R8, R10 and R11 are as defined for Formula (I).
Compounds of the invention having a structure Formula (IA) represent the xanthone derivatives of the present invention.
The present invention also embraces compounds of Formula (I), wherein R and Ar are as defined for Formula (I) above and wherein R2 and R3 are each independently selected from:
(i) a substituted or unsubstituted, preferably aromatic, carbocyclic or heterocyclic group containing from 5 to 10 ring atoms, said ring atoms forming one or two rings, wherein the or each ring contains 5 or 6 ring atoms, any heteroatoms being selected from N, O and S, any substituents being independently selected from the group consisting of
Cl, Br, F. OH, NO2, CF3, C1-4, lower alkyl (in particular CH3), SCH3, NHCOCH3, N(R6)(R8), OR10 and OCOR11, wherein R6, R8. R10 and R11 are as defined above,
(ii) Cl, (iii) Br, (iv) F. (v) OH, (vi) NO2, (vii) a saturated or unsaturated lower C1-6 straight or branched hydrocarbyl group which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from Cl, Br, F, OMe, NO2 and CF3, (viii) NHCOCH3, (ix) N(R6)(R8), (x) SR10, (xi) OR10, and (xii) OCOR11 wherein R6, R8, R10 and R11 are as defined above.
Such compounds include flavone derivatives according to the present invention. One preferred class of compounds according to Formula (I) are those wherein Ar, R and R3 are as defined in the above paragraph and wherein R2 represents
a substituted or unsubstituted, preferably aromatic, carbocyclic or heterocyclic group containing from 5 to 10 ring atoms, said ring atoms forming one or two rings, wherein the or each ring contains 5 or 6 ring atoms, any heteroatoms being selected from N, O and S, any substituents being independently selected from the group consisting of Cl, Br, F, OH, NO2, CF3, C1-4 lower alkyl (in particular CH3), SCH3, NHCOCH3, N(R6)(R8), OR10 and OCOR11, wherein R6, R8, R10 and R11 are as defined as for Formula (I) above,
represent flavone derivatives according to the present invention.
Preferably for the above described compounds, R3 is selected from the group consisting of
Cl, Br, F, OH, NO2, a saturated or unsaturated lower C1-6 straight or branched hydrocarbyl group which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from:
Cl, Br, F, OMe, NO2 and CF3;
NHCOCH3, N(R6)(R8), SR10, OR10 and OCOR11, wherein R6, R8,(R10 and R11 are as defined for Formula (I) above.
In a further preferred group of compounds according to the present invention, R2 represents:
a substituted or unsubstituted, preferably aromatic, carbocyclic or heterocyclic group containing from 5 to 10 ring atoms, said ring atoms forming one or two rings, wherein the or each ring contains 5 or 6 ring atoms, any heteroatoms being selected from N, O and S, any substituents being independently selected from the group consisting of:
Cl, Br, F, OH, NO2, CF3, C1-4 lower alkyl (in particular CH3), SCH3, NHCOCH3, N(R6)(R8), OR10 and OCOR11, wherein R6, R8, R10 and R11 are as defined in claim 1; and
R3 is selected from the group consisting of
Cl, Br, F, OH, NO2, a saturated or unsaturated lower C1-6 straight or branched hydrocarbyl group which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from:
Cl, Br, F, OMe, NO2 and CF3, NHCOCH3, N(R6)(R8), SR10, OR10 and OCOR11, wherein R6, R8, R10 and R11 are as defined above.
A further preferred group of compounds according to the present invention include compounds wherein
R3 is selected from:
Cl, Br, F, OH, NO2, CF3, C1-4 lower alkyl, SCH3, NHCOCH3, N(R6)(R8), OR10, and OCOR11 wherein R6, R8, R10 and R11 are as defined for Formula (I) above.
A particularly preferred R3 group is C1-4 lower alkyl, especially methyl.
In a further preferred class of compounds, R2 preferably represents a substituted or unsubstituted (preferably aromatic) carbocyclic group containing from 5 to 10 ring atoms, said ring atoms forming one or two rings, wherein the or each ring contains 5 or 6 ring atoms, and any substituents are independently selected from the group consisting of
Cl, Br, F, OH, NO2, CF3, C1-4 lower alkyl (in particular CH3), SCH3, NHCOCH3, N(R6)(R8), OR10 and OCOR11, wherein R6, R8, R10 and R11 are as defined above.
Of these, R2 preferably represents an unsubstituted, preferably aromatic, carbocyclic group containing from 5 to 10 ring atoms, said ring atoms forming one or two rings. An especially preferred R2 group is phenyl.
For the compounds of Formula (I), Ar preferably represents phenyl which may be unsubstituted or substituted with one or more substituents selected from the group consisting of Cl, Br, F, OH, NO2, CF3, C1-4 lower alkyl (in particular CH3), SCH3, NHCOCH3, N(R6)(R8), OR10 and OCOR11 wherein R6, R8, R10 and R11 are as defined for Formula (I).
Particularly preferred Ar groups include phenyl or phenyl substituted with 1, 2 or 3 methoxy groups.
For the Ar, R2 and R3 groups of Formula (I), the R10 and R11 groups are preferably a saturated or unsaturated C1-6 a straight chain or branched hydrocarbyl group. Particularly preferred groups include methyl, ethyl, n-propyl and iso-propyl. An especially preferred group is methyl.
The group R of the compounds of the invention preferably represents the group OR10. Within this group of compounds, preferred OR10 groups include xe2x80x94OCH2CHxe2x95x90CMe2,xe2x80x94OCH2CMexe2x95x90CH2, xe2x80x94OCH2CHxe2x95x90CH2 and xe2x80x94OCH2Cxe2x89xa1CH.
A further preferred group of compounds of the invention are compounds of Formula (I) wherein
Ar represents
phenyl, which may be unsubstituted or substituted by one, two or three substituents independently selected from
Cl, Br, F, OMe, NO2, CF3, C1-4 lower alkyl (in particular CH3), NMe2, NEt2, SCH3 and NHCOCH3;
thienyl, 2-furyl, 3-pyridyl, 4pyridyl or indolyl; and
R represents
OH or OCH2R1, wherein R1 is selected from xe2x80x94CHxe2x95x90CMe2, xe2x80x94CMexe2x95x90CH2, xe2x80x94CHxe2x95x90CH2 and xe2x80x94Cxe2x89xa1CH.
Within this group of compounds, Ar is preferably selected from trimethoxyphenyl, 3-pyridyl, 4pyridyl and 3indolyl, and R is preferably selected from OCH2CHxe2x95x90CMe2, OCH2CMexe2x95x90CH2, OCH2CHxe2x95x90CH2 and OCH2Cxe2x89xa1CH.
In a preferred class of compounds, Ar contains a basic nitrogen function, for example, by virtue of a heterocyclic nitrogen ring atom being present, or Ar may contain a substituent having a basic nitrogen, such as an amine, or an acetamido function. Thus a preferred Ar group is a substituted or unsubstituted, preferably aromatic, heterocyclic group, said heterocyclic group containing from 5 to 10 ring atoms, at least one of which is a nitrogen atom, said ring atoms forming one or two rings, with the or each ring containing 5 or 6 ring atoms, wherein any substituent on the ring is as defined as for Formula (I). A further preferred group of compounds is wherein the group Ar is substituted with at least one substituent selected from NHCOCH3 or N(R6)(R8), wherein R6 and R8 are the same or different and each represents H or lower C1-4 alkyl.
Particularly preferred Ar groups containing a basic nitrogen function include of 3-pyridyl, 4-pyridyl, 3-indolyl, 4-dimethylaminophenyl and 4-acetamidophenyl.
It will be appreciated that compounds of Formula (I) which contain a basic amino function may be converted to acid addition salts, with pharmacologically acceptable acids, e.g. hydrochloric acid and phosphoric acid. Such salts are also included in the present invention.
The present invention also provides the use of a compound of Formula (I) in the manufacture of an antiproliferative medicament In particular, the compounds of the present invention may be useful for the manufacture of a medicament for the treatment or prevention of neoplasms, particularly those located in the uterus, ovary or breast In particular, the compounds may be useful for the manufacture of a medicament for the treatment of cancer cells that are resistant to paclitaxel and docetaxel.
The compounds of Formula (I) may advantageously be used in combination therapies involving the combined use of a compound of Formula (I) and another anti-neoplastic agent, especially paclitaxel or docetaxel. The combination therapy may involve simultaneous or successive administration of a compound of Formula (I) and an anti-neoplastic agent Such combination therapy forms a further aspect of the invention.
The compounds of the invention may be further used in the manufacture of a medicament for the treatment or prevention of menopausal disorders and osteoporosis.
The present invention further includes a pharmaceutical composition comprising one of more of the compounds of Formula I in combination with one or more pharmaceutically acceptable excipients.
The invention will now be described by way of illustrative examples and with reference to the accompanying formulae drawings.